Water-compatible hydrogen-bond activation: a scalable and organocatalytic model for the stereoselective multicomponent aza-Henry reaction.

The water paradigm has changed in organic chemistry. Multiple organic reactions have been implemented in the form of watercompatible processes with a net gain in efficiency and instrumental simplicity. Most of these reactions are currently performed either as homogeneous solutions or easily-stirred aqueous suspensions. Homogeneity requires either the use of water soluble reactants or the aid of an organic co-solvent and are governed by hydrophobic and/or hydrogen-bond (H-bond) interactions. Aqueous suspensions involve reactants that are insoluble in water and at least one of them is a liquid (the socalled “on water” or in the presence of water conditions). Although there is no general agreement on the chemical bases governing these reactions nor the exact place where they occur, experimental evidences suggest that these reactions must be occurring at the organic-water interface, and as a consequence, they should be influenced by the properties of water molecules and reactants at these interfaces. Although several protocols based on covalent organocatalysis have been successfully developed in water or in the presence of water, the implementation of non-covalent based protocols has proved to be more problematic due to the polar properties of the water molecule and its hydrogen bond disruptor capacity. However, recent reports have shown that the development of these reactions can be feasible in a productive manner. In a seminal communication, Schreiner and col. established that hydrogen bonding thiourea-based catalysis can be accomplished in the presence of water and even amplified by hydrophobic hydration. More recently, Rueping and col. reported the first example of an asymmetric BrØnsted acid-catalyzed organic reaction in the presence of water, using the hydrophobic hydration as the driving force of the reaction. Although it is well established that water should favour multicomponent reactions (MCR), the number of successfully developed water-compatible MCR remains scarce. However, the implementation of robust and efficient water-compatible MCR manifolds still remains challenging. We describe herein our efforts in the development and implementation of the first example of an H-bond based organocatalytic multicomponent manifold operating “in the presence of water” conditions. The manifold performs a multicomponent and stereoselective version of the organocatalyzed aza-Henry reaction (Scheme 1A) and it utilizes aniline, aromatic or aliphatic aldehydes, primary or secondary nitroalkanes, N,N-dimethylcyclohexylamine as the catalytic base and a chiral thiourea or squaramide catalyst as the chiral source to afford the corresponding α,β-disubstituted βnitroamine derivatives 3 in good yield and high stereoselectivity (up to ≥99.5:0.5 e.r. and ≥99.5:0.5 d.r., anti-adduct). The catalysis is performed through H-bond interactions between the nitroalkane and the chiral catalyst. Importantly, each family of catalysts delivers the β-nitroamine 3 with complementary enantioselectivity, allowing for the selective access to the two enantiomeric series of these important building blocks in an efficient, instrumentally simple and scalable manner.